Injured mammalian tissues typically heal by a combination of regeneration and repair. Regeneration results in the re-establishment of the original tissue structure and function. In contrast, tissue repair entails the replacement of the original tissue with a patch of connective tissue, or scar, which is functionally and aesthetically inferior to the original (Ferguson M W et al., Scar-free healing: from embryonic mechanisms to adult therapeutic intervention, Philos Trans R Soc Lond B Biol Sci, 2004 May 29, 359(1445), 839-850.) The response of most mammalian tissues to injury falls within this spectrum, with some tissues that are believed not to regenerate at all. Regardless of the final outcome—scar or regenerated tissue, wound healing occurs in several stages.
Idiopathic Pulmonary Fibrosis (“IPF”) is a hypertrophic scarring response that is initiated following an insult to the alveolar epithelium in the lungs. The local response to the insult initiates the recruitment and proliferation of fibroblasts and myofibroblasts that then form micronodules of scar tissue throughout the affected lung, not unlike the keloid formation in skin. Kuhn, C., 3rd, et al., An immunohistochemical study of architectural remodeling and connective tissue synthesis in pulmonary fibrosis, Amer Rev. of Resp. Dis., 1989, 140, 1693-1703. Once the process is initiated, IPF follows an inevitably fatal course. The mean survival following diagnosis is 2.8 years and the five-year survival is under 12%. The incidence of IPF is estimated at 42 cases per 100,000 population, virtually the same as ovarian or pancreatic cancers. Raghu, G., et al., Incidence and prevalence of idiopathic pulmonary fibrosis, American journal of respiratory and critical care medicine, 2006, 174, 810-816; American Cancer Society, Cancer facts & figures 2006. At present the therapeutic options are quite limited: there are no agents that effectively alter the course of the disease.
Cyclosporine A (“CSA”) was originally developed as an immunosuppressant to prevent solid organ graft rejection in organ transplant recipients. The immunomodulatory activity of cyclosporine is exerted through its tight binding to the calmodulin-dependent, serine/threonine protein phosphatase, calcineurin (Liu J et al., Calcineurin is a common target of cyclophilin-cyclosporine A and FKBP-FK506 complexes, Cell, 1991 Aug. 23, 66(4), 807-815.) In T cells, calcineurin/cyclosporine complexes bind to and prevent the nuclear translocation of the nuclear factor of activated T cell (“NFAT”) protein, and thus its binding to the interleukin 2 (“IL-2”) promoter. This results in a failure to activate IL-2 production, putting an early block on the cellular immune cascade (Harding, 1989; Liu et al., 1991; Schreiber S. et al., Cytokine pattern of Langerhans cells isolated from murine epidermal cell cultures, J Immunol. 1992 Dec. 1, 149(11), 3524-3534; Siekierka J J et al., FK-506 and cyclosporin A: immunosuppressive mechanism of action and beyond, Curr Opin Immunol, 1992 Oct. 4(5), 548-552. In addition to T cells, NFAT is also highly expressed in stem cells in a number of tissues from embryogenesis through adulthood (Friday B B et al., Calcineurin activity is required for the initiation of skeletal muscle differentiation, J Cell Biol, 2000 May 1, 149(3), 657-666; Horsley V et al., Regulation of the growth of multinucleated muscle cells by an NFATC2-dependent pathway, J Cell Biol, 2001 Apr. 16, 153(2), 329-38; Horsley V et al., NFAT: ubiquitous regulator of cell differentiation and adaptation, J Cell Biol, 2002 Mar. 4, 156(5), 771-774; Li X et al., Calcineurin-NFAT signaling critically regulates early lineage specification in mouse embryonic stem cells and embryos, Cell Stem Cell, 2011 Jan. 7, 8(1), 46-58; Zhu L et al., Foxd3 suppresses NFAT-mediated differentiation to maintain self-renewal of embryonic stem cells, EMBO Rep, 2014 December, 15(12), 1286-1296), where it suppresses stem cell differentiation (Horsley V et al., 2002.) This immune suppression and stem cell differentiation modification may be useful in wound healing.
A compound that has been shown to promote wound healing is RT175 (AMG-474-00, GM1485, GPI 1485). RT175 (AMG-474-00, GM1485, GPI 1485) is a 241 Dalton molecule having the following chemical structure
RT175 binds with high affinity to FK506 binding protein 4 (“FKBP52”). FKBP52 is known to act as a molecular chaperone for the glucocorticoid receptor (“GR”). After binding to a ligand, the RT175/GR complex translocates to the nucleus (Banerjee A., et al. Control of glucocorticoid and progesterone receptor subcellular localization by the ligand-binding domain is mediated by distinct interactions with tetratricopeptide repeat proteins, Biochemistry, 2008, 47, 10471-10480.) It has been shown that that RT175 treatment of fibroblasts for 2 hours results in the translocation of FKBP52 to the nucleus, presumably with its cargo.
Current wound healing compositions include several inflammation factor compositions such as activated protein C (U.S. Patent Application Publication No. 2014/0219991), hsp90a (U.S. Pat. No. 8,455,443), and FAK inhibitors (U.S. Patent Application Publication No. 2013/0165463) and extracellular matrix replacement such as hyaluronic acid (U.S. Patent Application Publication No. 2015/0064129), sodium hyaluronate (U.S. Pat. No. 8,426,384), zinc gluconate, sodium hyaluronate and collagen (U.S. Pat. No. 9,125,892.)
Due to a lack of effective treatments, there is a need in the art for methods and compositions useful for treating pulmonary fibrosis.